New findings in mice suggest that bone affects the development of diabetes. A product of osteoblasts, undercarboxylated osteocalcin (ucOC), functions as a hormone regulating insulin sensitivity and production, an unexpected connection that promises new insights into insulin resistance, obesity and diabetes. The effect of ucOC is particularly noteworthy because it increases both insulin production and insulin sensitivity in mouse models. OC knock-out mice were obese with increased rates of diabetes and triglyceride levels and reduced insulin sensitivity and insulin production. An ESP knock-out mouse exhibited increased levels of ucOC, with normal OC, and a phenotype that was a mirror image of the OC knock-out mice. This mouse had improved insulin sensitivity and production and was protected from obesity even with high fat feeding. However, it is not known if these mechanisms operate in humans. If found in clinical studies, this pathway connecting bone and energy metabolism could lead to new approaches for preserving insulin sensitivity and production with implications for prevention of diabetes. Translational studies are urgently needed to determine whether ucOC predicts changes in glucose and lipid metabolism in humans. Limited clinical data suggest that higher ucOC levels have negative effects on the skeleton. In order to assess the associations between ucOC and energy metabolism as well as bone density in a population of older adults, this research project will use data and biological specimens from the Health, Aging and Body Composition (Health ABC) study, a cohort of 3,075 men and women, white and African-American, aged 70-79 years at baseline. Osteocalcin and ucOC will be assayed in stored baseline serum among participants with incident diabetes (N=162) and in a random sample of the baseline cohort, stratified into those with prevalent diabetes (N=135), impaired glucose metabolism (N=135) and normoglycemia (N=135). The Health ABC study has nine years of longitudinal data that, with the addition of baseline ucOC assays, can be immediately used to test the hypotheses that increased ucOC will be associated prospectively with reduced risk of diabetes and with improvements in glucose and lipid metabolism. A case-cohort design, including the incident diabetes cases and those in the baseline sub-cohort without prevalent diabetes, will be used to assess whether ucOC levels predict diabetes development. Using the baseline sub-cohort that includes those with and without diabetes, the study will also determine whether ucOC levels at baseline predict changes in fasting glucose, A1C and insulin resistance, in lipids (serum triglycerides, total cholesterol, LDLc, HDLc, nonHDLc, and oxidized LDL), and in total fat mass and bone density measured by dual x-ray absorptiometry (DXA). Adiponection and leptin will be assessed as potential intermediaries in any associations between ucOC and these outcomes. This study promises to break new ground by assessing evidence that the bone product, undercarboxylated osteocalcin, has an effect on insulin sensitivity, body fat, and the development of diabetes in humans. PUBLIC HEALTH RELEVANCE: Project Narrative A new, and unexpected, finding in mice indicates that a hormone produced by bone cells, uncarboxylated osteocalcin (ucOC), improves insulin sensitivity in fat cells, increases insulin production by the pancreas, and reduces the risk of weight gain and development of diabetes. In order to determine if ucOC plays a similar role in humans, this research project will use data and serum specimens from an already established longitudinal study in older adults. This research project will determine if lower ucOC levels predict development of diabetes or increases in total body fat over nine years.